An ongoing concern of intervention research in the area of adolescent substance use and abuse is the varying impact of interventions on individuals. To understand why intervention effects vary, it is critical to broaden the scope of inquiry to include gene-by-environment interplay, including but not limited to the moderation of intervention impact by specific genes. The proposed research will examine G-E interplay by adding a large panel of candidate genes implicated in substance use to the PROSPER study, a prospective cohort study of preventative interventions'impact on adolescent substance use. PROSPER provides specific and repeated annual assessments of substance use and contributing environmental factors from 6th grade through early adulthood. The proposed research will create a data set of 3,000 participants with DNA and measures of substance use and abuse outcomes across adolescence and into early adulthood (dependency measures are included in early adulthood). Participants also reported on family environment at each wave, including measures of parental child management, parent-child affective relationship quality, parent-child joint activities, and family cohesion. A separately funded grant (DA018225, PI: Osgood) has used annual peer friendship nominations to construct intricate measures of peer micro-environments, including characteristics of immediate peer groups (obtained through self-report by each nominated youth in the school social network), unstructured time spent with these peers, characteristics of participants'cliques, and social isolation. These detailed assessments of family and peer environments provide the PROSPER study with the high quality measurement of environmental risk factors crucial to successful GxE research (Cardon, 2003;Rutter, 2009). These high quality measures, prospective longitudinal design, and large sample size combine to make the proposed project ideal for examining both gene-environment interactions (GxE), including those underlying varying impacts of interventions on substance use and abuse, and gene-environment correlations (rGE) that work together to influence substance use behaviors. Specifically, proposed research will a) examine the that extent to which specific genetic factors condition the impact of interventions on substance use behaviors, b) identify the interplay between specific genes and family and peer contextual processes as they contribute to substance use, and c) estimate the extent that the specific environment factors involved in G-E interplay vary from early adolescence to early adulthood. By laying a foundation for future research regarding "specific" genetic factors and "specific" environmental experiences as they jointly contribute to substance use, this work will inform the development of more effective interventions, thus helping to alleviate the many adverse outcomes related to drug use. PUBLIC HEALTH RELEVANCE: Adolescent substance abuse is a significant public health issue. While preventive interventions have been shown to reduce risks of substance use generally, their effectiveness varies across adolescents. The goal of the proposed research is to identify the role of specific genes in conditioning the effect of both preventative interventions and experiences in the family and peer domains through which such interventions are designed to affect adolescent outcomes. The long- term goal is to develop a framework for individual-tailored preventive interventions to optimize the ability to minimize risk for the development of substance use problems based on individualized genetic and environmental risk factors.